title: Enzyme-controlling medicines: introduction.
abstract: A short history of the research work of S. Okamoto and co-workers, for the previous 50 years, is briefly described. In the 1950s, when the physiologic role of fibrinolysis had not been established, they began to seek for compounds that inhibit the action of plasmin. They examined approximately 200 lysine derivatives and discovered epsilon aminocaproic acid (EACA) and tranexamic acid (t-AMCHA). In the 1970s, we selected thrombin as the target enzyme to be controlled; structure-activity relationship studies, taking arginine as the skeleton structure, led to the discovery of the selective thrombin inhibitor No. 205 (4-ethyl-1-[N2-(5-dimethylamino-1-naphthalenesulfonyl)-L-arginyl]- 1-piperidine), and further attempts to minimize the toxicity finally led to No. 805 (argatroban, MD-805, (2R,4R)-4-methyl-1-(N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-sulfo nyl]-L-arginyl)-2-piperidine carboxylic acid). Argatroban, without any cofactor, inhibits thrombin competitively. The high selectivity of the action of argatroban is promising for treating thrombosis in clinical practice. More recently, taking advantage of our knowledge obtained through previous studies, active center-directed plasmin inhibitors and a selective inhibitor of kallikrein have been found.
authors.affiliation: Kobe Research Projects on Thrombosis and Haemostasis, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Okamoto
authors.forename: A
authors.initials: A
authors.lastname: Hijikata-Okunomiya
authors.forename: K
authors.initials: K
authors.lastname: Wanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
authors.forename: U
authors.initials: U
authors.lastname: Okamoto
mesh_terms: D015119:Aminocaproic Acid / Q000627:therapeutic use; D000933:Antifibrinolytic Agents / Q000627:therapeutic use*; D000991:Antithrombins / Q000009:adverse effects / Q000627:therapeutic use; D001120:Arginine / Q000031:analogs & derivatives; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D010875:Pipecolic Acids / Q000009:adverse effects / Q000627:therapeutic use; D013449:Sulfonamides; D014148:Tranexamic Acid / Q000627:therapeutic use
chemical_list: D000933:Antifibrinolytic Agents; D000991:Antithrombins; D004791:Enzyme Inhibitors; C101005:PASI 535; D010875:Pipecolic Acids; D013449:Sulfonamides; D010649:Phenylalanine; D014148:Tranexamic Acid; D001120:Arginine; D007610:Kallikreins; C031942:argatroban; D015119:Aminocaproic Acid